Cholinesterase Inhibitors In Liposomes And Their Production And Use

a technology of cholinesterase inhibitors and liposomes, which is applied in the direction of biocide, drug compositions, active ingredients of phosphorous compounds, etc., can solve the problems of insufficient local ngf concentration, less successful studies in this regard, and blockage or enhancement of the effect of acetylcholine on the receptor

Inactive Publication Date: 2008-02-07
SANOCHEMIA PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] Thus, the task in accordance with the invention is to find a way to administer cholinesterase inhibitors that have known effect on neuronal nicotinic receptors and / or NGF-like neurotropic activity in order to reduce or avoid both the known disadvantages of patch applications (for example, the need for a surface that is as flat as possible for application of the patch; possible skin irritations; active agent concentration in patch must be very high; penetration enhancers can cause skin damage) and the disadvantages of invasive administration methods and other systemic modes of use, in particular the undesirable systemic side effects that are linked to the necessary high dosage.

Problems solved by technology

This effect arises with quite different concentrations of the relevant agent, takes place at different binding sites of the receptor, and can result in a blockage or an enhancement of the effect of acetylcholine on the receptor, in some cases even in dependence on the concentration of the cholinesterase inhibitor itself and / or on the acetylcholine concentration that exists at the same time.
However, studies in this regard were less successful, presumably because sufficiently high local NGF concentrations could not be achieved without systemic side effects (Anand, Prog Brain Res. 2004; 146: 477-92).
Moreover, nicotinic agonists have shown adverse effects in their therapeutic usefulness in this connection because of side effects like high blood pressure and neuromuscular paralysis.
Peripherally acting cholinesterase inhibitors proved to be unsuitable for analgesic therapy in humans, principally also because of the side effect problems (Ghelardini et al., Presynaptic Auto and Heteroreceptors in the Cholinergic Regulation of Pain.
Said systems therefore are not suitable for treatment of neuropathic pain or a reduction of the dermal sensory function due to neurodegeneration.

Method used

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  • Cholinesterase Inhibitors In Liposomes And Their Production And Use
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  • Cholinesterase Inhibitors In Liposomes And Their Production And Use

Examples

Experimental program
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Effect test

example 1

Preparation and Stability Testing of Galantamine Liposomes

[0048] Synthetic dipalmitoylphosphatidylcholine (DPPC, Genzyme, Switzerland) and cholesterol (Solvay, Netherlands) were used to prepare vesicles. Some experiments were carried out either with hen's egg phosphatidylglycerol (E-PG; Lipoid Co., Germany) or with stearylamine (Sigma, USA), in order to introduce positive or negative charges into the liposomal membrane. Galantamine (Sanochemia AG, Austria) was used as the free base or as HBr salt in the inclusion experiments. PBS (phosphate buffered saline) or citric acid in combination with sodium carbonate were used as buffer solutions.

[0049] The liposomes were preferably prepared by means of the shear-free crossflow injection technique in accordance with WO 02 / 36257. This technique is highly reproducible and enables the inclusion of any active agents into liposomes. This continuous, one-step method allows unilamellar liposomes with a lipid double layer membrane (“bilayer”) with...

example 2

Preparation and Comparison of Galantamine Preparations in the Form of Liposomes or Microemulsions with Variable Lipid Composition

[0076] Synthetic dipalmitoylphosphatidylcholine (DPPC, Genzyme, Switzerland), dimyristoylphosphatidylcholine (DMPC, Genzyme, Switzerland) and cholesterol (Solvay, Netherlands) were used as lipids in this example. Galantamine (Sanochemia AG, Austria) was used as the HBr salt for the liposomal inclusion studies. Citric acid / sodium carbonate was used as buffer solution.

[0077] The ammonium sulfate gradient method was employed as a second possibility for active loading. An ammonium sulfate solution and a glucose solution were used as aqueous phases for vesicle preparation. Once again, the crossflow technique was used. After removing unenclosed galantamine by gel filtration, both the active agent and lipid contents were determined by rp-HPLC. The liposome size and size distribution were again determined by photon correlation spectroscopy (PCS).

[0078] In addit...

examples 3-10

Skin Penetration Tests of Various Lipid-Based Galantamine Preparations Franz Diffusion Cell

[0109] The diffusion cell came from PermeGear, USA. The equipment consisted of three diffusion cells, each with a water-filled double jacket mounted on an agitator bracket and connected to a water bath for temperature control. The cells themselves had a receptor volume of 8 mL each, a skin holder with a surface area of 0.78 cm2 and a donor chamber with 2 mL volume.

[0110] Skin Integrity Test:

[0111] Pigskin was used for the tests in the Franz diffusion cell. In order to ensure an intact skin surface, each skin piece was tested before and after the experiment. After affixing the skin on the skin holder of the diffusion cell, 2 mL buffer was applied to the skin and it was heated to 32±1° C. After 30 minutes, the electrical conductivity, a measure of the resistance of the skin and quality of the skin, was measured. The measurement value is dependent on the origin of the skin, its thickness, the ...

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Abstract

The invention relates to a pharmaceutical composition based on an active ingredient that is enclosed in liposomes for topical, transdermal application. The interior of said liposomes comprises an acidic, aqueous medium containing at least one cholinesterase inhibitor, preferably from the group containing donepezil, rivastigmine, galantamine, physostigmine, heptylphysostigmine, phenserine, tolserine, cymserine, thiatolserine, thiacymserine, neostigmine, huperzine, tacrine, metrifonate and dichlorvos, or an enantiomer or derivative of at least one of said compounds. In addition, the invention relates to a method for producing said composition, optionally in a sterile form and also to the use of the liposomes charged with the active ingredient in various galenic formulations for topical, transdermal application with a depot effect in the epidermis, for the prophylaxis and/or treatment of cutaneous neuropathic pain or the loss of cutaneous sensory function as a result of neuropathy.

Description

TECHNICAL FIELD [0001] This invention concerns pharmaceutical compositions based on cholinesterase inhibitors in liposomes, the preparation of such compositions and their possibilities for use in therapy. BACKGROUND OF INVENTION [0002] Central cholinesterase inhibitors are used for pharmacotherapy of mild and moderate Alzheimer's disease in order to partially restore the diminished function of the cholinergic conduction pathway system in the brain that is produced in this syndrome. Recent research showed that many cholinesterase inhibitors not only block acetyl- and butyrylcholinesterases by various mechanisms, but also have direct effects on neuronal nicotinic acetylcholine receptors. These receptors, whose natural ligand is acetylcholine, are found not only on cholinergic nerves, but also in serotonergic and glutamatergic nerve systems, and they control the release of the relevant neurotransmitter there. [0003] This effect arises with quite different concentrations of the relevant...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/127A61K31/27A61K31/407A61K31/435A61P25/00A61K31/4353A61K31/55A61K31/661A61K9/00
CPCA61K9/127A61P9/00A61P17/00A61P25/00A61P25/02A61P25/28A61P29/00A61P43/00
Inventor BODENTEICH, ANGELIKABOCKMANN, JOSEFFRANTSITS, WERNERPIRICH, EBERHARDWAGNER, ANDREASVORAUER-UHL, KAROLA
Owner SANOCHEMIA PHARMA AG
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